Methods of inhibiting binding of beta-sheet fibril to rage and consequences thereof

Abstract

This invention provides a method of inhibiting the binding of beta-sheet fibril to RAGE on the surface of a cell which comprises contacting the cell with a binding-inhibiting amount of a compound capable of inhibiting binding of beta-sheet fibril to RAGE so as to thereby inhibit binding of beta-sheet fibril to RAGE.In one embodiment, the beta-sheet fibril is amyloid fibril. In one embodiment, the compound is sRAGE or a fragment thereof. In another embodiment, the compound is an anti-RAGE antibody or portion thereof.This invention provides the above method wherein the inhibition of binding of the beta-sheet fibril to RAGE has the consequences of decreasing the load of beta-sheet fibril in the tissue, inhibiting fibril-induced programmed cell death, and inhibiting fibril-induced cell stress.This invention also provides methods of determining whether a compound inhibits binding of a beta-sheet fibril to RAGE on the surface of a cell.

Description

[0001]This application is a continuation-in-part and claims priority of U.S. Ser. No. 09 / 374,213, filed Aug. 13, 1999, the contents of which are incorporated by reference.[0002]The invention disclosed herein was made with Government support under grant numbers AG00690, AG14103, AG12891, NS31220, HL56881, HL69091 from the USPHS, JDFI and the Surgical Research Fund. Accordingly, the government has certain rights in this invention.[0003]Throughout this application, various publications are referenced to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references may be found at the end of this application, preceding the claims.BACKGROUND OF THE INVENTION[0004]Amyloid beta-peptide (Aβ) engagement of cell surface receptors would be expected to have diverse consequences for cell function. Co...

AI Technical Summary

Benefits of technology

This patent describes a method for inhibiting the binding of β-sheet fibril to RAGE, a protein found on the surface of cells. This can help decrease the load of β-sheet fibril in tissue and prevent or treat diseases involving β-sheet fibril formation. The method involves contacting the cells with a compound that can inhibit the binding of β-sheet fibril to RAGE. The patent also provides a method for determining whether a compound inhibits the binding of β-sheet fibril to RAGE. The invention also includes a compound that has been determined to inhibit the binding of β-sheet fibril to RAGE.

Problems solved by technology

However, deposition of Aβ fibrils sets the stage for Alzheimer's disease (AD) in which accumulation of amyloidogenic material may be associated with neuronal toxicity and diminished synaptic density, ultimately leading to clinical dementia (Terry et al., 1991; Kosik, 1994; Funato et al., 1998; Selkoe, 1999).

The conditions used in the prior work were such that fibril formation was not possible.

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